Haloacetyl imidazoles

ABSTRACT

A series of 2-guanidino-4-heteroarylthiazoles, wherein the heteroaryl substituent is selected from thiazolyl, triazolyl, imidazolyl, and 2-alkyl, 2-amino and 2-carboxamido derivatives thereof, are disclosed. The novel compounds have activity as antisecretory agents and histamine H 2  antagonists and are useful for the treatment of gastric hyperacidity and peptic ulcers. Also disclosed are pharmaceutical compositions containing the novel compounds of this invention and a method of using the compounds in the treatment of gastric hyperacidity and peptic ulcers. Novel intermediates useful in the preparation of the novel antisecretory compounds are also described.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 293,574, filedAug. 20, 1981, now U.S. Pat. No. 4,374,843, which is acontinuation-in-part of U.S. patent application Ser. No. 196,231, filedOct. 14, 1980, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel 2-guanidino-4-heteroarylthiazoleshaving activity as antisecretory agents and histamine H₂ antagonists andwhich are accordingly useful in the prevention and treatment of gastrichyperacidity and peptic ulcers.

Chronic gastric and duodenal ulcers, together known as peptic ulcers,are a common ailment for which a variety of treatments, includingdietary measures, drug therapy and surgery, may be employed, dependingon the severity of the condition. Particularly valuable therapeuticagents useful for the treatment of gastric hyperacidity and pepticulcers are the histamine H₂ -receptor antagonists, which act to blockthe action of the physiologically active compound histamine at the H₂-receptor sites in the animal body and to thereby inhibit the secretionof gastric acid.

SUMMARY OF THE INVENTION

The present invention relates to novel 2-guanidino-4-heteroarylthiazolesuseful as histamine-H₂ antagonists and as antisecretory agents and whichare therefore useful in the treatment of peptic ulcers and otherconditions caused or aggravated by gastric hyperacidity. Morespecifically, the novel compounds of this invention are those of theformula ##STR1## wherein X is S or NH; Y is CH, C.CH₃ or N; R ishydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms, --(CH₂)_(n) Ar,--NH₂, --NHR₁ or --NHCOR₁, wherein R₁ is alkyl of 1 to 6 carbon atoms or--(CH₂)_(m) Ar; wherein n is an integer from 2 to 4; m is zero or aninteger from 1 to 4; and Ar is phenyl or phenyl monosubstituted withchloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3carbon atoms; provided that when Y is N, Y is NH and m is other thanzero; and when X is S, R is other than hydroxymethyl, alkyl or--(CH₂)_(n) Ar.

One group of compounds of interest are those wherein Y is CH and X is S,that is 2-guanidino-4-thiazolyl-thiazole and derivatives thereof.Preferred compounds include those where R is hydrogen, --NH₂, --NHCH₃and NHCOCH₃.

A further group of compounds of particular interest embraced by thepresent invention are those wherein Y is CH and X is NH, that is2-guanidino-4-imidazolyl-thiazole and derivatives thereof. Preferredcompounds include those wherein R is hydrogen, hydroxymethyl, methyl,--NH₂ ; --NHCH₃ or --NHCOCH₃, especially hydrogen, hydroxymethyl, methylor --NH₂.

Another group of compounds of this invention are those wherein Y isC.CH₃ and X is NH, that is2-guanidino-4-(4-methyl-5-imidazolyl)-thiazole and derivatives thereof.Preferred compounds include those wherein R is hydrogen or methyl.

Another group of compounds of the present invention are those wherein Yis N and X is NH, that is 2-guanidino-4-triazolyl-thiazole andderivatives thereof. Preferred compounds include those wherein R is--NH₂ or methyl.

Also embraced by the present invention are pharmaceutical compositionscomprising a gastric antisecretory effective amount of a compound offormula I, or a pharmaceutically acceptable acid addition salt thereof,together with a pharmaceutically acceptable carrier or diluent.Preferred pharmaceutical compositions are those containing the preferredcompounds of formula I as described hereinabove, including those whereinY is CH, X is S and R is --NH₂ ; Y is CH, X is NH and R is hydrogen,hydroxymethyl, methyl or --NH₂ ; and where Y is N, X is NH and R is--NH₂ or methyl.

The present invention also comprises the method of treating gastrichyperacidity in an animal in need of treatment comprising administeringto the animal a gastric antisecretory effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof. Preferredcompounds for use in this method of treatment are the preferredcompounds of formula I as described herein above.

The present invention also includes novel intermediates useful in thepreparation of the compounds of formula I. More particularly, suchcompounds are those of the formula ##STR2## and the acid addition saltsthereof, wherein R₂ is --COCH(R")R₃ or --CONHR₄, wherein R" is hydrogenor methyl, R₃ is halo, N₃ or --NH₂ and R₄ is --NH₂ or --NHC(NH)NH₂.

Further intermediates useful for the preparation of compounds of formulaI are those of the formula ##STR3## and the acid addition salts thereof,wherein R' is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbon atoms or--(CH₂)_(n) Ar, wherein n and Ar are as previously defined; R" ishydrogen or methyl; and R₅ is halo, preferably chloro or bromo.Preferred intermediates of formula III are those wherein R' is hydrogenor methyl and R₅ is chloro or bromo.

Further intermediates embraced by the present invention are the novel3-halo-4-n-alkoxy-3-buten-2-ones, wherein the n-alkoxy group has from 1to 4 carbon atoms, preferably methoxy or ethoxy, especially thecompounds where the halo group is chloro or bromo which are useful inthe preparation of the intermediates of formula III.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of formula I wherein Y is CH or C.CH₃ and X is NH orS are prepared from the corresponding novel intermediates of formula IIwherein R₂ is --COCH(R")R₃ and R₃ is halo, preferably chloro or bromo,most preferably bromo. Such intermediates where R₂ is --COCH₂ R₃ areprepared from a 1,4-dihalo-2,3-butane-dione, preferably1,4-dibromo-2,3-butanedione, by the reaction with an excess of atrialkylorthoformate, preferably triethylorthoformate, in the presenceof a catalytic amount of a strong acid, such as concentrated sulfuricacid, p-toluene sulfonic acid and the like, at temperature from about 0°C. to about 55° C., preferably from about 15° C. to about 25° C. The1,4-dihalo-2,2-dialkoxy-3-butanone produced is then reacted withN-amidinothiourea in an organic solvent, such as tetrahydrofuran,dioxane, ether and the like, at a temperature from about 0° C. to about55° C., preferably from about 20° C. to 50° C., to form2-guanidino-4-(2-halo-1,1-dialkoxyethyl)thiazole. The latter compound isheated in a hydrogen halide solution, preferably hydrogen bromide, at atemperature from about 0° C. to about 50° C., preferably from about 20°C. to about 30° C. to form the desired2-halo-1-(2-guanidino-4-thiazolyl)ethanone i.e. the intermediate offormula II, wherein R₂ is --COCH₂ R₃ and R₃ is halo, preferably bromo.Similarly, compounds of formula II wherein R₂ is --COCH(CH₃)R₃ may beprepared by the reaction of a 1-halo-2,3-pentanedione withN-amidinothiourea, as previously described, to form1-(2-guanidino-4-thiazolyl) propanone, which is then reacted with ahalogen in aqueous hydrogen halide solution, preferably with bromine inaqueous hydrobromic acid solution, to give the desired intermediates offormula II.

The compounds of formula I wherein Y is CH or C.CH₃ and X is S areprepared directly from an appropriate2-halo-1-(2-guanidino-4-thiazolyl)alkanone intermediate of formula II byreaction with an appropriate compound of the formula RC(S)NH₂. Forexample, reaction of the intermediate2-halo-1-(2-guanidino-4-thiazolyl)-ethanone with a thiourea or a N-R₁-substituted-thiourea yields compounds of formula I wherein Y is CH, Xis S and R is NHR₁, while reaction with thioformamide provides thecompound of formula I wherein Y is CH, X is S and R is hydrogen. Thereaction of the 2-halo-1-(2-guanidino-4-thiazolyl)alkanone with theappropriate compound of formula RC(S)NH₂ is generally conducted at atemperature from about 0° C. to about 30° C., preferably from about 20°C. to 30° C., in an inert solvent such as dimethylformamide or otherpolar organic solvents.

Alternatively, the compounds of formula I wherein Y is C.CH₃ and X is Smay be prepared by reaction of a 4-halo-2,3-pentanedione, preferably4-bromo-2,3-pentanedione, with an appropriate thioamide of the formulaRC(S)NH₂ to form a 2-R-4-acetyl-5-methyl-thiazole. These intermediatesmay be halogenated to the 2-halo-1-(2-R-5-methyl-4-thiazolyl) ethanones,which in turn may be reacted with N-amidinothiourea to afford compoundsof formula I where Y is C.CH₃ and X is S.

Alternatively, compounds of formula I wherein Y is CH, or C.CH₃, X is Sand R is --NHR₁ where R₁ is alkyl or aralkyl may also be prepared byreaction of the corresponding compounds of formula I wherein R is --NH₂with an alkyl or aralkyl halide in the presence of a base. Similarly,the compounds of formula I wherein Y is CH or C.CH₃, X is S and R is--NHCOR₁ may be prepared by the reaction of the corresponding compoundof formula I wherein R is --NH₂ by reaction with an appropriatecarboxylic acid halide or anhydride.

Compounds of formula I wherein Y is CH or C.CH₃ and X is NH may also beprepared from the previously described2-halo-1-(2-guanidino-4-thiazolyl)alkanone intermediates by firstforming the corresponding 2-azido-1-(2-guanidino-4-thiazolyl)alkanonei.e. the novel intermediate of formula II wherein R₂ is --COCH(R")R₃ andR₃ is N₃. The latter compound is formed by the reaction of the2-halo-1-(2-guanidino-4-thiazolyl)alkanone with an alkali metal azide,such as sodium or potassium azide, in a polar organic solvent such asdimethylformamide or other N,N-dialkylamides at a temperature from about0° C. to about 100° C., preferably from about 60° C. to about 100° C.,followed by addition of a base such as an alkali metal hydroxide or analkali metal carbonate, preferably sodium or potassium carbonate.

For the preparation of compounds of formula I wherein Y is CH or C.CH₃,X is NH and R is --NH₂ or --NHR₁, the2-azido-1-(2-guanidino-4-thiazolyl)ethanone is first reduced to thecorresponding 2-amino compound i.e. the novel intermediate of formula IIwherein R₂ is --COCH(R")R₃ and R₃ is --NH₂, for example by hydrogenationin the presence of a noble metal catalyst, such as palladium on carbon,or platinum oxide, in an aqueous lower alkyl alcohol solvent, preferablyaqueous methanol or ethanol, in the presence of a strong acid, such asconcentrated hydrochloric acid, sulfuric acid, p-toluene sulfonic acidand the like, at a temperature from about 15° C. to about 50° C.,preferably from about 20° C. to about 35° C. The2-amino-1-(2-guanidino-4-thiazolyl)alkanone is then reacted with anappropriate cyanamide of the formula H₂ NCN or R₁ NHCN, followed by theaddition of a base such as an alkali metal hydroxide or carbonate,preferably sodium or potassium carbonate, to provide compounds offormula I wherein Y is CH or C.CH₃, X is NH and R is --NH₂ or --NHR₁,respectively. The N-substituted cyanamides, R₁ NHCN, used in thisreaction can be readily prepared by reaction of the correspondingsubstituted amine with a cyanogen halide, such as cyanogen bromide orchloride. The reaction of the2-amino-1-(2-guanidino-4-thiazolyl)alkanone with cyanamide or theappropriate N-substituted cyanamide of the formula R₁ NHCN is generallyeffected at a temperature from about 15° C. to about 100° C., preferablyfrom about 70° C. to about 100° C., in aqueous solution at a pH betweenabout 4 and 5, preferably about 4.5.

Alternatively, compounds of formula I wherein Y is CH or C.CH₃, X is NHand R is --NHR₁ where R₁ is alkyl or aralkyl may also be prepared fromthe corresponding compounds of formula I wherein R is --NH₂ by reactionwith an alkyl or aralkyl halide in the presence of a base. Further, thecompounds of formula I wherein Y is CH or C.CH₃, X is NH and R is --NH₂may be reacted with an appropriate carboxylic acid halide or anhydrideto form the corresponding compounds of formula I wherein R is --NHCOR₁.

Compounds of formula I wherein Y is CH or C.CH₃, X is NH and R ishydrogen, hydroxymethyl, alkyl or --(CH₂)_(n) Ar are prepared from the2-amino-1-(2-guanidino-4-thiazolyl)alkanone by reaction with an alkylcarboximidate of the formula RC(NH)OR₆, where R₆ is alkyl of 1 to 3carbon atoms, preferably methyl or ethyl, or an acid addition saltthereof, for example the hydrogen halide salt, preferably thehydrochloride or hydrobromide salt. The reaction is generally conductedin a lower alkyl alcohol solvent, preferably methanol or ethanol, at atemperature from about 0° C. to 70° C. The compound so formed is thenconverted to the desired compound of formula I wherein Y is CH, X is NHand R is hydrogen or alkyl by heating in the presence of an acid, suchas hydrochloric acid, sulfuric acid, p-toluene sulfonic acid and thelike, followed by the addition of a base such as an alkali metalhydroxide or carbonate, preferably sodium or potassium carbonate.Alternatively, the 2-azido-1-(2-guanidino-4-thiazolyl)alkanone may bereacted with a trialkylorthoformate to form the corresponding1,1-dialkoxy derivative, which is then reduced to the 2-amino compoundand reacted with an alkyl carboximidate, as previously described.

The compounds of formula I wherein Y is N and X is NH may be preparedfrom 2-guanidino-4-thiazole carboxylic acid hydrazide i.e. the novelintermediate of formula II wherein R₂ is --CONHR₄ and R₄ is --NH₂. Thisintermediate is prepared by the reaction of an alkyl halopyruvate,preferably ethyl bromopyruvate, with N-amidinothiourea in an organicsolvent, such as a lower alkyl alcohol of 1 to 4 carbon atoms,preferably methanol or ethanol, at a temperature from about 0° C. toabout 100° C., preferably at the reflux temperature of alcohol solvent,to form a 2-guanidino-4-thiazole carboxylic acid alkyl ester. The latteris then reacted with hydrazine in a lower alcohol solvent, preferablyabsolute ethanol, at a temperature from about 0° C. to about 100° C.preferably at the reflux temperature of the alcohol solvent, to form thedesired 2-guanidino-4-thiazole carboxylic acid hydrazide.

The hydrazide derivative formed as described above is reacted with analkyl carboximidate of the formula RC(NH)OR₆, where R₆ is alkyl of 1 to3 carbon atoms, preferably methyl or ethyl, or an acid addition saltthereof, preferably a hydrohalide such as the hydrochloride orhydrobromide salt, to form the corresponding 2-guanidino-4-thiazolecarboxylic acid 2-carboximinohydrazide. The reaction is conducted in aninert organic solvent, preferably a lower alkyl alcohol, such asmethanol or ethanol, in the presence of a base, such as an alkali metalalkoxide, preferably sodium or potassium ethoxide, at a temperature fromabout 10° C. to about 100° C., preferably from about 20° C. to 75° C.The 2-guanidino-4-carboxylic acid 2-carboximinohydrazide is then heatedat a temperature from about 75° C., to about 110° C., preferably fromabout 90° C. to 100° C., in concentrated ammonia solution to form thedesired compound of formula I wherein Y is N and X is NH.

The compounds of formula I wherein Y is N, X is NH and R is --NH₂ may beformed from the 2-guanidino-4-thiazole carboxylic acid hydrazidepreviously described by reaction with 2-methylthiopseudourea H₂NC(SCH₃)NH, or an acid addition salt thereof, such as the hydrohalide,preferably the hydrochloride or hydrobromide, or the hemisulfate, toform 2-guanidino-4-thiazole carboxylic acid 2-amidinohydrazide i.e. thenovel intermediate of formula II wherein R₂ is --CONHR₄ and R₄ is--NHC(NH)NH₂. The reaction is generally conducted in an organic solventsuch as dimethylsulfoxide at a temperature from about 150° C. to about225° C., preferably about 180° C. to about 200° C. The product is thenheated at a temperature from about 75° C. to about 110° C., preferablyabout 90° C. to about 100° C., in concentrated ammonia solution to formthe desired compound of formula I wherein Y is N, X is NH and R is--NH₂.

The compounds of formula I where Y is N, X is NH and R is --NH₂ may bereacted with an appropriate alkyl or aralkyl halide in the presence of abase to form the corresponding compounds of formula I wherein R is--NHR₁ where R₁ is alkyl or aralkyl. Similarly, such compounds where Ris --NH₂ may be converted to the corresponding compounds where R is--NHCOR₁ by reaction with an appropriate carboxylic acid halide oranhydride.

An alternative method of preparing the compounds of formula I wherein Ris hydrogen, alkyl or (CH₂)_(n) Ar is by the reaction of an intermediateof the formula ##STR4## wherein R' is hydrogen, hydroxymethyl, alkyl or--(CH₂)_(n) Ar, where n and Ar are as previously defined, and R₅ ishalo, with N-amidinothiourea in an organic solvent such astetrahydrofuran, ether, a lower alkyl alcohol such as methanol orethanol and the like at a temperature from about 0° C. to about 75° C.This method of preparation is of particular interest for the preparationof compounds of formula I wherein X is NH and Y is CH or C.CH₃. Theintermediates of formula IV wherein X is NH and Y is CH or C.CH₃ (i.e.the compounds of formula III as previously described) may be prepared byhalogenation of the corresponding 2-R'-5-R"-4-acetyl-imidazole where R"is hydrogen or methyl, for example by reaction with a halogen in anaqueous hydrogen halide solution, preferably with bromine in aqueoushydrobromic acid.

The 2-R'-5-R"-4-acetyl imidazole for use in this reaction may beprepared by irradiation of 1-acetyl-2-R'-5-R"-imidazole withultra-violet light. Alternatively, 2-R'-4-acetyl-imidazoles may beprepared by reaction of a 3-halo-4-n-alkoxy-3-buten-2-one, especiallythe 3-chloro- or 3-bromo-compound, with an appropriate R'-substitutedamidine of the formula R'C(NH₂)NH or a salt thereof in the presence of abase such as a trialkylamine, preferably triethylamine, in an organicsolvent such as acetone, tetrahydrofuran, dioxane and the like, at atemperature from about 0° C. to about 100° C., preferably at refluxtemperature in tetrahydrofuran.

The 3-halo-4-n-alkoxy-3-buten-2-one starting materials may be preparedfrom the known 3-halo-4-hydroxy-3-buten-2-one by reaction with adialkylsulfate or diazoalkane in, for example, aqueous tetrahydrofuranor dioxane, in the presence of a weak base such as an alkali metalbicarbonate at a temperature from about 0° C. to about 60° C.,preferably from about 15° C. to 30° C. Alternatively, the3-halo-4-n-alkoxy-3-buten-2-one may be prepared by heating a3-halo-4-hydroxy-3-buten-2-one at reflux with an appropriate n-alkanol,for example in toluene solution.

The preparation of corresponding intermediates of formula IV for thepreparation of other compounds of formula I i.e. having other X and Ygroups, may be prepared by reactions analogous to those describedhereinabove by the use of appropriately substituted starting materials.

The pharmaceutically acceptable acid addition salts of the novelcompounds of formula I are also embraced by the present invention. Thesalts are readily prepared by contacting the free base with anappropriate mineral or organic acid in either aqueous solution or in asuitable organic solvent. The solid salt may then be obtained byprecipitation. or by evaporation of the solvent. The pharmaceuticallyacceptable acid addition salts of this invention include, but are notlimited to, the hydrochloride, sulfate, bisulfate, mesylate, nitrate,phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate,succinate, gluconate and the like. Preferred salts are the hydrochlorideand dihydrochloride. If desired, the compounds of formula I as the freebase may be formed from the acid addition salts thereof by treatmentwith an appropriate base followed by extraction of the free base with asuitable organic solvent.

The compounds of formula I and the pharmaceutically acceptable acidaddition salts thereof have activity as antisecretory agents andhistamine H₂ antagonists and accordingly are of therapeutic value in thetreatment of gastric hyperacidity and peptic ulcers. For the purposes ofthe present specification and claims hereof the term treatment ofgastric hyperacidity is meant to include the treatment of peptic ulcersand other such conditions caused by, or aggravated, by the secretion ofgastric acid. The compounds may be administered to a subject in need oftreatment by a variety of conventional routes of administrationincluding orally and parenterally. Preferably, the compounds areadministered orally. In general, these compounds will be administeredorally at doses between about 0.1 to 20 mg/kg body weight of the subjectto be treated per day, preferably from about 0.2 to 2.5 mg/kg per day.If parenteral administration is desired, then these compounds can begiven at doses between about 0.1 and 1.0 mg/kg body weight of thesubject to be treated per day. However, some variation in dosage willnecessarily occur depending upon the condition of the subject beingtreated and the particular compound employed.

The compound may be administered alone or in combination withpharmaceutically acceptable carriers or diluents, in either single ormultiple doses. Suitable pharmaceutical carriers include inert diluentsor fillers, sterile aqueous solutions and various organic solvents. Thepharmaceutical compositions formed by combining the novel compounds offormula I or salts thereof and pharmaceutically acceptable carriers arereadily administered in a variety of dosage forms such as tablets,powders, capsules, lozenges, syrups and the like. These pharmaceuticalcompositions can, if desired, contain additional ingredients such asflavorings, binders, excipients and the like. Thus, for oraladministration, tablets containing various excipients, such as sodiumcitrate, may be employed, together with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matters or dyesand, if desired, emulsifying agents or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin, orcombinations thereof.

Preferably, the novel compounds of this invention are administeredorally in unit dosage form, i.e. as a single physically discrete dosageunit containing an appropriate amount of the active compound incombination with a pharmaceutically acceptable carrier or diluent.Examples of such unit dosage forms are tablets or capsules containingfrom about 5 to 1,000 mg of the active ingredient, the compound offormula I comprising from about 10% to 90% of the total weight of thedosage unit.

For parenteral administration, solutions of the compounds of formula Iin sterile aqueous solutions, for example aqueous propylene glycol,sodium chloride, dextrose or sodium bicarbonate solutions may beemployed. Such solutions should be suitably buffered if necessary andthe liquid diluent first rendered isotonic with sufficient saline orglucose. The preparation of suitable sterile liquid media for parenteraladministration will be well known to those skilled in the art.

The activity of the compounds of the present invention as antisecretoryagents and histamine-H₂ antagonists may be determined by standardpharmacological tests, including for example (1) measuring their abilityto antagonize the actions of histamine which are not blocked by anantihistamine such as mepyramine and (2) measuring their ability toinhibit gastric acid secretion in the stomachs of Heidenhain pouch dogsthat had previously been treated with pentagastrin in order to stimulatethe secretion of gastric acid.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples. All temperatures are in degreescentigrade.

EXAMPLE 1 1,4-Dibromo-2,2-diethoxy-3-butanone

A mixture of 40 g (0.164 mol) of 1,4-dibromo-2,3-butanedione, 60 ml(0.36 M) of triethylorthoformate, and 2 ml of concentrated sulfuric acidwas stirred at room temperature for 14 hours, then diluted with 600 mlof chloroform, and washed successively with 100 ml portions of water,0.5 N hydrochloric acid and saturated sodium chloride solution. Theorganic solution was dried over anhydrous sodium sulfate filtered, andevaporated leaving an oil. The oil was taken up into 300 ml of hexaneand filtered to remove some insoluble material. The hexane filtrate wascooled in a dry-ice/acetone bath, and the resulting precipitate wascollected by filtration and dried to give 44 g (84%) of1,4-dibromo-2,2-diethoxy-3-butanone as a white crystalline solid, mp40°-41.5°; nmr (CDCl₃) (δ): 4.50 (s, 2H); 3.6-3.2 (m, 6H); 1.22 (t, 6H).

EXAMPLE 2 2-Guanidino-4-(4-bromo-1,1-diethoxyethyl)thiazole

A mixture of 25.5 g (80 mmol) of 1,4-dibromo-2,2-diethoxy-3-butanone,11.8 g (100 mmol) of N-amidinothiourea, and 150 ml of tetrahydrofuranwas heated at reflux for 3 hours. The mixture was filtered to removesome insoluble solid, and the filtrate was concentrated. The residue wastriturated with 200 ml of saturated sodium bicarbonate, then extractedfour times with a total of 500 ml of ethyl acetate. The combined ethylacetate extracts were dried over sodium sulfate, filtered and evaporatedleaving a solid. Recrystallization from 250 ml of acetonitrile, afterdecolorization with charcoal, afforded 9.7 g (36%) of2-guanidino-4-(2-bromo-1,1-diethoxyethyl)thiazole as a white solid, mp157°-158°; calcd. for C₁₀ H₁₇ N₄ O₂ SBr: C, 35.62; H, 5.08; N, 16.61;Br, 23.69; S, 9.51; found: C, 35.60; H, 4.97; N, 16.99; Br, 23.75; S,9.59.

EXAMPLE 3 2-Bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide

A mixture of 9.5 g (28 mmol) of2-guanidino-4-(2-bromo-1,1-diethoxyethyl)thiazole in 50 ml of 48%hydrobromic acid was stirred at room temperature for 15 hours. Themixture was evaporated to complete dryness to afford 10.1 g (100%) of2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide mp 247° (dec).This material could be converted to the free base by triturating withsaturated sodium bicarbonate, stirring for 15 minutes, filtering thesolid, and drying it under vacuum. In this way, 3.0 g of thehydrobromide salt was converted to 1.7 g (88%) of the free base, mp 210°(dec); nmr (DMSO-d₆ (δ): 7.84 (s, 1H); 6.92 (s, 4H); 4.78 (s, 2H).

EXAMPLE 4 2-Guanidino-4-(2-amino-4-thiazolyl)thiazole dihydrobromide

A solution of 688 mg (2.0 mmol) of2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide and 183 mg ofthiourea in 5 ml of dimethylformamide was stirred at room temperature.After a short time, a solid began to precipitate. After a total of fourhours, the solid was collected by filtration, washed with ethyl acetate,and dried, thereby affording 595 mg (74%) of2-guanidino-4-(2-amino-4-thiazolyl)thiazole dihydrobromide as a whitepowder; mp 320° (dec); mass spectrum parent of 240. This material couldbe converted to its free base by triturating with saturated sodiumbicarbonate solution, stirring for 15 minutes, filtering the solid, anddrying it under vacuum. In this way2-guanidino-4-(2-amino-4-thiazolyl)thiazole was obtained as acrystalline solid, mp 274°. Calcd. for C₇ H₈ N₆ S₂ : C, 34.99; H, 3.36;N, 34.97; found: C, 34.94; H, 3.41; N, 34.80.

EXAMPLE 5 2-Guanidino-4-(4-thiazolyl)thiazole

A mixture of 1.8 g (5.2 mmol) of2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 0.34 g (5.5mmol) of thioformamide, and 10 ml of dimethylformamide was stirred atroom temperature for 2 hours. The mixture was concentrated and theresidue was triturated with acetonitrile. The resulting precipitate wascollected by filtration, washed with acetonitrile, and dried to afford1.74 g (85%) of 2-guanidino-4-(4-thiazolyl)thiazole dihydrobromide. Thiswas dissolved in 10 ml of water, and 1 ml of saturated sodiumbicarbonate solution was added. The resulting precipitate was collectedby filtration, washed well with water, then acetonitrile, then dried invacuo to afford 1.17 g of 2-guanidino-4-(4-thiazoyl)thiazole as a whitesolid, mp 220°-222°; nmr (DMSO-d₆) (δ): 8.96 (s, 1H); 7.96 (s, 1H); 7.18(s, 1H); 7.0 (b, 4H); calcd. for C₇ H₇ N₅ S₂ : C, 37.32; H, 3.13; N,31.09; found: 36.94; H, 3.52; N, 29.74.

EXAMPLE 6 2-Guanidino-4-(2-N-methylamino-4-thiazoyl)thiazole

A mixture of 1.77 g (5.14 mmol) of2-bromo-1-(2-guanidino-4-thiazoyl)ethanone hydrobromide, 0.49 g (5.5mmol) of N-methylthiourea, and 10 ml of dimethylformamide was stirred atroom temperature for 18 hours. The mixture was concentrated and theresidue was triturated with a small amount of acetonitrile. The crudesolid was collected by filtration, then dissolved in water. The aqueoussolution was made basic with saturated sodium bicarbonate solution andthe resulting precipitate was collected by filtration and allowed todry. Recrystallization from ethanol/water afforded 0.70 g (54%) of2-guanidino-4-(2-N-methylamino-4-thiazoyl)thiazole as a white solid, mp267°; nmr (DMSO-d₆ (δ): 7.44 (q, 1H); 7.0-6.9 (s+s+b, 6H); 2.85 (t, 3H);calcd. for C₈ H₁₀ N₆ S₂ : C, 37.77; H, 3.96; N, 33.05; found: C, 38.01;H, 4.47: N, 32.84.

EXAMPLE 7 2-Guanidino-4-(2-N-acetylamino-4-thiazoyl)thiazole

A mixture of 1.77 g (5.14 mmol) of2-bromo-1-(2-guanidino-4-thiazoyl)ethanone hydrobromide, 0.65 g (5.5mmol) of N-acetylthiourea, and 10 ml of dimethylformamide was stirred atroom temperature for 18 hours. The mixture was concentrated and theresidue triturated with acetonitrile. The resulting solid was collectedby filtration, then added to 50 ml of saturated sodium bicarbonatesolution and stirred for 1 hour. The solid was collected by filtrationand allowed to dry. Recrystallization from ethanol/water afforded 1.0 g(68%) of 2-guanidino-4-(2-N-acetylamino-4-thiazoyl)thiazole as a whitesolid, mp 288°; nmr (DMSO-d₆) (δ): 7.40 (s, 1H); 7.0-6.9 (b, 5h); 3.2(b, 1H); 2.22 (s, 3H); calcd. for C₉ H₁₀ N₆ OS₂ : C, 38.28; H, 3.57; N,29.77; found: C, 38.13; H, 4.07; N, 29.41.

EXAMPLE 8 2-Guanidino-4-thiazole carboxylic acid ethyl ester

111.2 g (0.94 mol) of 2-amidinothiourea was dissolved in 1 liter ofrefluxing ethanol. To the refluxing solution was rapidly added over a 10minute period 200 g (1.02 mol) of ethyl bromopyruvate. After 2 hours ofreflux an additional 20 g (0.1 mol) of ethyl bromopyruvate was added andreflux was continued for an additional 2 hours. The reaction was cooledto 10° and concentrated ammonium hydroxide solution was added to raisethe pH to 10. A solid formed and was collected by filtration, washedtwice with ether and dried in vacuo to give 176.4 g (88%) of2-guanidino-4-thiazole carboxylic acid ethyl ester, mp 229°-230° (dec.).

EXAMPLE 9 2-Guanidino-4-thiazole carboxylic acid hydrazide

16.7 g (0.0779 mol) of 2-guanidino-4-thiazole carboxylic acid ethylester was combined with 25 ml (0.514 mol) of hydrazine hydrate in 200 mlabsolute ethanol. The slurry was heated to reflux. After 1.5 hour refluxa solid began to form from the clear solution. After 2 hours reflux thereaction slurry was cooled and the resulting solid was collected byfiltration and was washed with isopropyl alcohol and ether to give 12.8g (82%) 2 guanidino-4-thiazole carboxylic acid hydrazide, mp 247°(dec.).

EXAMPLE 10 2-Guanidino-4-thiazole carboxylic acid 2-amidinohydrazidehemisulfate

17.9 g (0.089 mol) of 2 guanidino-4-thiazole carboxylic acid hydrazidewas combined with 24.9 g of 2-methyl-2-thiopseudourea sulfate (0.089mol) and heated rapidly to reflux in 125 ml dimethylsulfoxide. Thereactants dissolved and within 5 minutes reflux a heavy precipitateformed. Reflux was continued for a total of 30 minutes. The reaction wascooled and the resulting heavy precipitate was isolated by filtrationand washed with a small portion of dimethylsulfoxide followed by washingwith isopropyl alcohol and ether. The resulting solid was dried in vacuoto give 34.6 g of 2-guanidino-4-thiazole carboxylic acid2-amidinohydrazide containing some occluded dimethylsulfoxide.

EXAMPLE 11 2-Guanidino-4-(3-amino-5-1,2,4-triazolyl)thiazole

29.1 g (0.1 mol) of 2-guanidino-4-thiazole carboxylic acid 2-amidinohydrazide hemisulfate was heated to boiling with 250 ml concentratedammonium hydroxide. Additional ammonium hydroxide was added to replacethe volume lost due to loss of ammonia. After 8 hours heating, boilingwas continued until the pH was below 8.0 and the mixture was allowed tocool. The resulting solid was collected by filtration, washed with asmall portion of water, decolorized with charcoal, recrystallized fromwater and dried in vacuo to give 10.8 g (48%) of2-guanidino-4-(3-amino-5-1,2,4-triazolyl)thiazole, mp 173°-5°. nmr(DMSO-D₆) (δ): 7.07 (s, 1H); 6.93 (broad s, 4H); 5.53 (broad s, 2H);Calcd. for C₆ H₈ N₈ S: C, 32.14; H, 3.60; N, 49.97; found: C, 32.13; H,3.70; N, 50.15.

EXAMPLE 12 2-Guanidino-4-thiazole carboxylic acid 2-acetiminohydrazide

37.1 g (0.3 mol) of ethyl acetimidate hydrochloride was dissolved in 200ml absolute ethanol. A solution of sodium ethoxide (6.9 g (0.3 mol)sodium in 300 ml absolute ethanol) was added. The resulting precipitateof sodium chloride was removed by filtration and to the clear filtratewas added 20.0 g (0.1 mol) of 2-guanidino-4-thiazole carboxylic acidhydrazide. The slurry was stirred at 25° for 60 hours, during which timecomplete dissolution occurred. The clear, pale orange solution wasconcentrated in vacuo to a soft solid which was triturated in 10:1 ethylacetate-ethanol to give 24.0 g (88%) of crude 2-guanidino-4-thiazolecarboxylic acid 2-acetiminohydrazide, with a broad melting point, 150°to 178° (dec.).

EXAMPLE 13 2-Guanidino-4-(3-methyl-5-1,2,4-triazolyl)thiazolehemihydrate

23.0 g (0.095 mol) of 2-guanidino-4-thiazole carboxylic acid2-acetiminohydrazide was heated to boiling with 200 ml concentratedammonium hydroxide solution. Additional ammonium hydroxide was added toreplace the volume lost due to loss of ammonia. After 7 hours heating,boiling was continued until the pH was below 8.0 and the mixture wasallowed to cool. The resulting solid was collected by filtration, washedwith a small portion of water and then dried (110°/0.1 mm Hg) for 24hours to give 8.6 g (39%)2-guanidino-4-(3-methyl-5-(1,2,4-triazolyl)thiazole hemihydrate mp 185°(loss of H₂ O), 260° (dec.). nmr (DMSO-d₆) (δ): 7.22 (s, 1H); 6.90(broad s, 4H), 3.50 (broad s, 1H--H₂ O); 2.32 (s, 3H); Calcd. for C₇ H₉N₇ S.1/2H₂ O: C, 36.19; H, 4.34; N, 42.22; found: C, 36.43; H, 4.29; N,42.17.

EXAMPLE 14 2-Guanidino-4-thiazole carboxylic acid 2-butyriminohydrazide

2.90 g (14.48 mol) of 2-guanidino-4-thiazole carboxylic acid hydrazidein 50 ml dry ethanol was slurried with 29.1 mmol of ethyl butyrimidate(prepared from 4.41 g (29.1 mmol) of ethylbutyrimidate hydrochloride)for 5 days at 25°. The slurry was filtered and washed with ethanol andether and dried to give 3.071 g (78%) of 2-guanidino-4-thiazolecarboxylic acid 2-butyriminohydrazide.

EXAMPLE 15 2-Guanidino-4-(3-propyl-5-1,2,4-triaziolyl)thiazolehemihydrate

2.547 g (9.5 mmol) of 2-guanidino-4-thiazole carboxylic acid2-butyriminohydrazide was heated at reflux in 50 ml water for 2 hours.The reaction was cooled and the resultant solid was recrystallized from150 ml of a 4:1 water:ethanol solution to give 1.119 g (47%) of2-guanidino-4-(3-propyl-5-1,2,4-triazolyl)thiazole hemihydrate, mp268°-270° (dec.). nmr (DMSO-d₆) (δ): 13.68 (broad s, 1H); 7.18 (s, 1H);6.90 (broad s, 4H); 2.64 (t, 2H); 1.70 (m, 2H); 0.90 (t, 3H); Calcd. forC₉ H₁₃ N₇ S.1/2H₂ O: C, 41.52; H, 5.42; N, 37.66; found: C, 41.81; H,5.50; N, 38.10.

EXAMPLE 16 2-Guanidino-4-thiazole carboxylicacid-2-propioniminohydrazide

2.90 g (14.48 mmol) of 2-guanidino-4-thiazole carboxylic acid hydrazidein 50 ml dry ethanol was slurried with 29.1 mmol of ethyl propionimidate(prepared from 4.0 g (29.1 mmol) of ethyl propionimidate hydrochloride)for 5 days at 25°. The slurry was filtered and the resulting solid wasdried for 2 hours at 60° in vacuo to give 2.802 g (75%) of2-guanidino-4-thiazole carboxylic acid 2-propioniminohydrazide.

EXAMPLE 17 2-Guanidino-4-(3-ethyl-5-1,24-triazolyl)thiazole

2.726 g (10.7 mmol) of 2-guanidino-4-thiazole carboxylic acid2-propioniminohydrazide was heated at reflux in 50 ml water for 2 hours.On cooling a solid precipitated. This was treated with 200 ml boilingwater, a small quantity of insoluble material was removed and thesolvent was cooled to afford a white solid. Two additionalrecrystallizations from water gave 1.048 g (41%) of2-guanidino-4-(3-ethyl-5-1,2,4-triazolyl)thiazole, mp 251°-7° (dec.).nmr (DMSO-d₆) (δ): 13.80 (broad s, 1H); 7.27 (s, 1H); 6.95 (broad s,4H); 2.70 (q, 2H); 1.25 (t, 3H); Calcd. for C₈ H₁₁ N₇ S: C, 40.49; H,4.67; N, 41.32; found: C, 40.61; H, 4.60; N, 40.50.

EXAMPLE 18 2-Azido-1-(2-guanidino-4-thiazolyl)ethanone

A mixture of 50 g (0.14 mol) of2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 23.6 g (0.36mol) of sodium azide, and 250 ml of dimethylformamide was stirred atroom temperature for 1.5 hours. The mixture was poured into 1.5 litersof water, and the aqueous solution was made basic with solid sodiumcarbonate. The resulting precipitate was filtered, washed well withwater, and dried, thereby affording 30.6 g (93%) of2-azido-1-(2-guanidino-4-thiazolyl)ethanone as a light brown crystallinesolid, mp 177° (dec). Analytically pure material can be prepared byrecrystallization from absolute ethanol: Calcd. for C₆ H₇ N₇ OS: C,32.00; H, 3.13; N, 43.53; S. 14.24; found: C, 32.22; H, 3.43; N, 41.93;S, 13.97.

EXAMPLE 19 2-Amino-1-(2-guanidino-4-thiazolyl)ethanone.dihydrochloride

A mixture of 12.0 g (53 mmol) of2-azido-1-(2-guanidino-4-thiazolyl)ethanone, 1.0 g of 10% palladium oncarbon, 100 ml of ethanol, 50 ml of water, and 20 ml of concentratedhydrochloric acid was hydrogenated at 3 atm. and room temperature for 1hour. At this point another 50 ml of water and 300 mg of 10% palladiumon carbon was added to the mixture and hydrogenation was continued at 3atm for another 0.75 hour. The mixture was diluted with 200 ml of water,filtered to remove the catalyst, and the filtrate concentrated leaving13.1 g (92%) of 2-amino-1-(2-guanidino-4-thiazolyl)ethanonedihydrochloride as a white powder mp>270°. nmr (DMSO-d₆) (δ): 8.58 (b,4H) 8.44 (s, 1H); 4.58 (b, 4H).

EXAMPLE 20 2-Guanidino-4-(2-amino-4-imidazolyl)thiazole

A mixture of 43 g (0.15 mol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochlorde, 12.6 g (0.30mol) of cyanamide, and 400 ml of water was brought to pH 4.5 by thedropwise addition of 20% sodium hydroxide solution. The mixture washeated at 50°-60° for 16 hours. The mixture was cooled, made basic withaqueous sodium carbonate solution and the resulting precipitate wascollected by filtration, then washed successively with cold water,acetone, and ether. The dried solid was purified by dissolving in aminimum of dimethylformamide, then slowly adding ethyl acetate.Initially tarry material precipitated which was removed by decanting.Further addition of ethyl acetate afforded 16 g of a tan solid. This wasagain purified by the dimethylformamide-ethyl acetate proceduredescribed above to give 12 g of a tan solid. Recrystallization of thismaterial from methanol/water afforded analytically pure title compoundas tan needles, mp 267° (dec). Calcd. for C₇ H₉ N₇ S: C, 37.66; H, 4.06;N, 43.91; S, 14.36; found: C, 37.81; H, 4.31; N, 43.76.

EXAMPLE 21 2-Guanidino-4-(2-N-methylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 0.62 g (11mmol) of N-methylcyanamide, and 10 ml of water was brought to pH 4.5 bythe dropwise addition of 20% sodium hydroxide solution. The mixture washeated at 50° for 16 hours. The mixture was cooled, made basic withaqueous sodium carbonate solution and the resulting precipitate wascollected by filtration, then washed successively with cold water,acetone, and acetonitrile. The crude solid was converted to itsdihydrochloride salt by dissolving it in a minimum amount of saturatedmethanolic hydrogen chloride, then slowly adding ether. Initially tarprecipitated and this was removed by decanting. Further addition ofether resulted in the precipitation of a crystalline solid which wasfiltered and dried. Recrystallization from methanol/ether afford 190 mg(10%) of the pure title compound, mp 280°; nmr (DMSO-d₆) (δ): (freebase) 6.86 (b, 5H); 6.77 (s, 1H); 6.45 (s, 1H); 5.60 (b) (1H); 2.68 (d,3H); calcd. for C₈ H₁₁ N₇.2HCl.H₂ O: C, 29.27; H, 4.61; N, 29.87; found:C, 30.01; H, 4.81; N, 29.78.

EXAMPLE 22 2 -Guanidino-4-(2-N-ethylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 4.0 g (15 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 1.54 g (22mmol) of N-ethylcyanamide, and 20 ml of water was brought to pH 4.5 bythe dropwise addition of 20% sodium hydroxide solution. The mixture washeated at 50° for 16 hours. The mixture was cooled, made basic withaqueous sodium carbonate solution and the resulting precipitate wascollected by filtration and washed successively with cold water, andacetone. The crude solid was converted to its dihydrochloride salt bydissolving it in a minimum about of saturated ethanolic hydrogenchloride, filtering away insolubles, then slowly adding ether. Theresulting precipitate was collected by filtration, washed with ether anddried. Recrystallization from ethanol/ether afforded 0.46 g (10%) of thetitle compound mp 235°; nmr (DMSO-d₆) (δ): 8.42 (b, 5H); 7.99 (t, 1H);7.87 (s, 1H); 7.65 (s, 1H); 3.43 (m, 2H); 1.19 (t, 3H); calcd. for C₉H₁₃ N₇ S.2HCl.H₂ O: C, 31.58; H, 4.71; N, 28.65; found: C, 31.11; H,5.38; N, 27.79.

EXAMPLE 23 2-Guanidino-4-(2-N-n-propylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride. 0.92 g (11mmol) of N-n-propylcyanamide, and 20 ml of water was brought to pH 4.5by the dropwise addition of 20% sodium hydroxide solution. The mixturewas heated at 50° for 16 hours, then cooled, made basic with aqueoussodium carbonate solution and filtered to remove some insolublematerial. The filtrate was concentrated and the residue was trituratedwith 50 ml of ethanol and filtered to remove insoluble material.Concentration of the filtrate afforded a crude solid which was convertedto its dihydrochloride salt by dissolving in saturated ethanolichydrogen chloride, filtering away some insoluble material, and dilutingthe filtrate with ether. The resulting precipitate was filtered, washedwith ether and dried. Recrystallization from ethanol/ether afforded 180mg (7%) of the pure title compound, mp 227°-229°; nmr (DMSO-d₆) (δ):8.40 (b, 6H); 7.86 (s, 1H); 7.64 (s, 1H); 3.40 (m, 2H); 1.62 (m, 2H);0.09 (t, 3H); calcd. for C₁₀ H₁₅ N₇ S.2HCl.H₂ O: C, 33.71; H, 5.38; N,27.52; found: C, 33.75; H, 5.03; N, 26.41.

EXAMPLE 24 2-Guanidino-4-(2-N-i-propylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 0.92 g (11mmol) of N-i-propylcyanamide, and 20 ml of water was brought to pH 4.5by the dropwise addition of 20% sodium hydroxide solution. The mixturewas heated at 60° for 16 hours. Another 0.30 g (3.7 mmol) ofN-i-propylcyanamide was added and the mixture was heated at 110° for 3hours. The mixture was made basic with aqueous sodium carbonate solutionand filtered to remove some insoluble material. The filtrate wasconcentrated and the residue was triturated with 50 ml of ethanol andfiltered to remove inorganics. Concentration of the filtrate afforded acrude solid which was converted to its dihydrochloride salt bydissolving in saturated ethanolic hydrogen chloride, filtering awayinsoluble material, and diluting the filtrate with ether. The resultingprecipitate was filtered, washed with ether and dried. Recrystallizationfrom ethanol/ether afforded 0.34 g (13%) of the pure title compound, mp138° ; nmr (DMSO-d₆) (δ): 8.39 (b, 6H); 7.82 (s, 1H); 7.59 (s, 1H); 3.10(m, 1H); 1.05 (d, 6H): calcd. for C₁₀ H₁₅ N₇ S.2HCl.H₂ O: C, 33.71; H,5.38; N, 27.52; found: C, 33.71; H, 5.97; N, 26.15.

EXAMPLE 25 2-Guanidino-4-(2-N-n-butylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazoyl)ethanone dihydrochloride, 1.08 g (11mmol) of N-n-butylcyanamide; and 20 ml sodium hydroxide solution. Themixture was heated at reflux for 60 hours, then cooled, made basic withaqueous sodium carbonate solution, then concentrated. The solid residuewas triturated with methanol, filtered to remove insolubles, and thefiltrate concentrated leaving an oil. The oil was taken up in 20 ml ofethanolic hydrogen chloride, filtered again to remove insolubles, andthe filtrate was diluted with ether. The resulting precipitate wascollected by filtration, washed with ether, and dried in vacuo to afford0.25 g (10%) of 2-quanidino-4-(2-N-n-butylamino-4-imidazoyl)thiazoledihydrochloride mp 224°-228°; nmr (DMSO-d₆) (δ): 8.40 (b, 6H); 7.82 (s,1H); 7.60 (s, 1H); 3.40 (m, 2H); 1.8-1.3 (m, 4H); 0.97 (t, 3H).

EXAMPLE 26 2-Guanidino-4-(2-N-benzylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 1.45 g (11mmol) of N-benzylcyanamide, and 20 ml of water was brought to pH 4.5 bythe dropwise addition of 20% sodium hydroxide solution. The mixture washeated at 60° for 16 hours. Another 0.48 g (3.7 mmol) ofN-benzylcyanamide was added and the mixture was heated at 110° for 20hours. The mixture was cooled to room temperature, then made basic withaqueous sodium carbonate. The resulting precipitate was collected byfiltration, washed with water, and allowed to dry. The solid was stirredin 60 ml of methanol, filtered to remove insolubles, and the filtrateconcentrated. The residue was taken up into 40 ml of ethanolic hydrogenchloride, filtered to remove precipitate amounted to 1.5 g (51%) of thepure title compound, mp 174°; nmr (DMSO-d₆) (δ): 8.41 (b, 6H); 7.94 (s,1H); 7.72 (s, 1H); 7.6-7.1 (m, 5H); 4.72 (d, 2H); calcd. for C₁₄ H₁₅ N₇S.2HCl.H₂ O: C, 41.58; H, 4.74; N, 24.25; found: C, 41.97; H, 5.43; N,23.80.

EXAMPLE 27 2-Guanidino-4-(2-N-phenethylamino-4-imidazoyl)thiazoledihydrochloride

A mixture of 2.0 g (7.3 mmol) of2-amino-1-(2-guanidino-4-thiazoyl)ethanone dihydrochloride, 1.61 g (11mmol) of N-phenethylcyanamide, and 20 ml of water was brought to pH 4.5by the dropwise addition of 20% sodium hydroxide solution. The mixturewas heated at 60° for 16 hours. Another 0.54 g (3.7 mmol) ofN-phenethylcyanamide was added and the mixture was heated at 110° for 20hours. The mixture was cooled to room temperature, then made basic withaqueous sodium carbonate. The resulting precipitate was collected byfiltration, washed with water, and allowed to dry. The solid was stirredin 60 ml of methanol, filtered to remove insolubles, and the filtrateconcentrated. The residue was taken up into 40 ml of ethanolic hydrogenchloride, filtered to remove insolubles and the filtrate diluted with200 ml of ether. The resulting precipitate amounted to 0.62 g (20%) ofthe pure title compound, mp 187°; nmr (DMSO-d.sub. 6) (δ): 8.48 (b, 6H);7.94 (s, 1H); 7.70 (s, 1H); 7.38 (s, 5H); 3.72 (m, 2H); 2.96 (t, 3H):calcd. for C₁₅ H₁₇ N₇ S.2HCl.H₂ O: C, 43.06; H, 5.06; N, 23.44; found:C, 42.36; H, 5.13; N, 23.30.

EXAMPLE 28 2-Guanidino-4-(2-N-acetamido-4-imidazoyl)thiazole

A mixture of 1.0 g (4.5 mmol) of2-guanidino-4-(2-amino-4-imidazoyl)thiazole 0.35 (4.5 mmol) of acetylchloride, and 10 ml of pyridine was stirred at room temperature for 2.5hours. The supernatant solution was decanted from an insoluble residueand poured into 20 ml of water. This aqueous solution was concentratedand the crude solid residue was triturated with 4 ml of water. Theresulting solid was filtered, and dried to give 0.18 g (16%) of thetitle compound, mp 151°-155°; nmr (DMSO-d₆): (δ) 7.38 (s, 1H); 7.2-6.8(b, 6H); 6.76 (s, 1H); 1.97 (s, 3H). Recrystallization fromethanol/ether afforded analytically pure product; mp 159°-160°; calcd.for C₉ H₁₁ N₇ OS.H₂ O: C, 38.15; H, 4.62; N, 34.60; found: C, 38.09; H,4.21; N, 34.88.

EXAMPLE 29 4-Acetylimidazole

A mixture of 6.0 g (54 mmol) of 1-acetylimidazole in 60 ml oftetrahydrofuran was photolyzed in a Rayonet reactor using a quartzvessel at 30° for 16 hours. The mixture was concentrated and the residuechromatographed over 100 g of silica gel using 19:1 chloroform/methanolas eluent. The less polar product was 2-acetylimidazole, mp 133°-135°(0.32 g, 5%). The more polar product amounted to 1.1 g (19%) of4-acetylimidazole, mp 165°-168°.

EXAMPLE 30 2-Bromo-1-(4-imidazoyl)ethanone hydrobromide

A solution of 0.50 g (4.5 mmol) of 4-acetylimidazole in 10 ml ofmethanol was stirred a room temperature and 10 drops of 48% hydrogenbromide was added. After stirring at room temperature for 15 minutes, 50ml of absolute ether was added and the resulting precipitate wascollected by filtration and dried to give 0.54 g of the hydrobromidesalt, mp 214° (dec). This was dissolved in 10 ml of 48% hydrogenbromide, warmed to 60° and 0.15 ml (3.0 mmol) of bromine was added.After stirring at 60° for 1 hour, the mixture was concentrated and theresidue triturated with a mixture of isopropanol/ether. The whitecrystalline precipitate was filtered, washed with ether, and dried togive 0.42 g (35%) of 2-bromo-1-(4-imidazoyl)ethanone hydrobromide, mp188°-192°. nmr (DMSO-d₆) (δ): 9.02 (s, 1H); 8.45 (s, 1H); 4.84 (s, 2H).

EXAMPLE 31 2-Guanidino-4-(4-imidazoyl)thiazole hydrobromide

A mixture of 0.38 g (1.4 mmol) of 2-bromo-1-(4-imidazoyl)ethanonehydrobromide in 10 ml of acetone was warmed until homogeneous, then 0.17g (1.4 mmol) of amidinothiourea was added and the mixture was heated atreflux for 0.5 hour. The mixture was cooled and the white precipitatewas collected, washed with ether, and dried, thereby affording 0.24 g(60%) of 2-guanidino-4-(4-imidazoyl)thiazole hydrobromide, mp 225°(dec). nmr (DMSO-d₆) (δ): 8.20 (s, 1H); 8.0 (b, 4H); 7.77 (s, 1H); 7.36(s, 1H); high resolution mass spectrum: calcd. C₇ H₈ N₆ S: for 208.0531;found: 208.517; calcd. for C₇ H₈ N₆ S.HBr.H₂ O: C, 27.37; H, 3.60; N,27.36; found: C, 27.23; H, 3.57; N, 27.64.

EXAMPLE 32 2-Guanidino-4-(4-imidazoyl)thiazole

A mixture of 42 ml of concentrated sulfuric acid and 21 ml of water wascooled to -10° and 1.56 g (22.7 mmol) of sodium nitrate was added. Afterstirring at -5° for ten minutes, 8.1 ml (78 mmol) of cold 50%hypophosphorous acid was added and stirring was continued for another 10minutes at -5°. A solution of 2.5 g (8.4 mmol) of2-guanidino-4-(2-amino-4-imidazoyl)thiazole dihydrochloride in 100 ml ofwater was added dropwise over 0.5 hour. The reaction was stirred at 50°for 2 hours, then at room temperature for 16 hours. The reaction mixturewas diluted with 500 ml of water, made basic with solid sodium carbonateand extracted three times with 150 ml portions of ethyl acetate. Thecombined ethyl acetate extracts were dried over sodium sulfate,filtered, and evaporating leaving a solid. This solid was taken up intoboiling methanol, decolorized with charcoal, and concentrated to a smallvolume. The resulting solid was collected and dried, thereby affording90 mg (5%) of 2-guanidino-4-(4-imidazoyl)thiazole identical to thematerial of Example 31 by thin layer chromatography and high resolutionmass spectrometry.

EXAMPLE 33 3-Bromo-4-methoxy-3-buten-2-one

5.0 g (30 mmol) of 3-bromo-4-hydroxy-3-buten-2-one was dissolved in asolution of 100 ml tetrahydrofuran and 10 ml water. To the solution wasadded 8.7 ml (90 mmol) of dimethylsulfate and 8.3 g (100 mmol) of sodiumbicarbonate. The slurry was stirred at 25° for 75 minutes and thesolvent was removed in vacuo. The resultant oil and solid were stirredovernight in a mixture of 20 ml diethylether and 150 ml 0.1 N sodiumbicarbonate solution. The aqueous layer was separated and extracted with2×50 ml ether and the combined ether extracts were washed with saturatedsodium chloride solution, dried over anhydrous sodium sulfate andconcentrated in vacuo to a yellow oil which soon solidified to afford3.21 g (59%) of 3-bromo-4-methoxy-3-buten-2-one, mp 53°-6°. nmr(DMSO-d₆) (δ): 8.22 (s, 1H); 4.03 (s, 3H); 2.37 (s, 3H); Calcd. for C₅H₇ BrO₂ : C, 33.55; H, 3.94; Br, 44.64; found: C, 33.27; H, 3.85; Br,43.46.

EXAMPLE 34 1-(2-methyl-4-imidazolyl)ethanone

6.3 g (35 mmol) of 3-bromo-4-methoxy-3-buten-2-one, 16.7 g acetamidinehydrochloride (175 mmol) and 29.2 ml triethylamine (210 mmol) werecombined in 300 ml tetrahydrofuran and heated at reflux for 6 hours. Thesolvent was removed in vacuo to a crude orange solid. The crude solidwas dissolved in 200 ml ethyl acetate and concentrated to 25 ml byboiling off the solvent. Cooling in ice resulted in crystallization of ayellow solid. This was collected by filtration, washed first with ethylacetate, then with ether and dried at 25° in vacuo to give 9.995 g (23%)of 1-(2-methyl-4-imidazolyl)ethanone, mp 124°-7°. nmr (DMSO-d₆) (δ):4.61 (s, 1H); 1.41 (s, 3H); 1.39 (s, 3H).

EXAMPLE 35 1-(2-methyl-4-imidazolyl)ethanone

5.75 g (46.3 mmol) of 1-(2-methyl-1-imidazolyl)ethanone was dissolved in600 ml tetrahydrofuran and photolyzed in a quartz flask with a shortwave u.v. light source (2537 nm) for 18 hours. The tetrahydrofuransolution was concentrated in vacuo to an oil and chromatographed onsilica gel using 5% methanol in chloroform as eluent to give 2.6 g (45%)1-(2-methyl-4-imidazolyl)ethanone, mp 123°-5°.

EXAMPLE 36 1-(2-Methyl-4-imidazolyl)-2-bromoethanone hydrobromide

2.40 g (19.3 mmol) of 1-(2-methyl-4-imidazolyl) ethanone was dissolvedin 30 ml of 48% hydrogen bromide. To the stirred solution at 25° wasadded over a 5 minute period 3.36 g (21 mmol) of bromine dissolved in 5ml 48% hydrogen bromide. The reaction was heated to 70° for 2.5 hoursand then concentrated in vacuo to a dark oil. A mixture of isopropylalcohol/ether was added and trituration of the oil gave a solid. Thiswas collected by filtration and washed with ether to give 2.8 g (51%) of1-(2-methyl-4-imidazolyl)-2-bromoethanone hydrobromide, mp 181° (dec.);nmr (DMSO-d₆) (δ): 8.71 (s, 1H); 4.77 (s, 2H); 2.63 (s, 3H).

EXAMPLE 37 2-Guanidino-4-(2-methyl-4-imidazolyl)thiazole

2.8 g (9.86 mmol) of 1-(2-methyl-4-imidazolyl)-2-bromo ethanonehydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonatesolution was added to pH 10 and the resultant solid was collected byfiltration and washed with 15 ml water. The dried free base was heatedat reflux in 50 ml acetone. To the refluxing clear acetone solution wasadded 1.2 g (9.86 mmol) of amidinothiourea. Solution occurredimmediately and within a minute a solid began to form. After 1 hourreflux the slurry was cooled and the solid was collected by filtrationand was washed with acetone followed by ether to give 2.37 g (79%) of2-guanidino-4-(2-methyl-4-imidazolyl)thiazole hydrobromide, mp 158°(dec.); nmr (DMSO-d₆) (δ): 7.71 (s shoulder on broad s, 1H); 7.56 (broads, 4H); 4.32 (s, 1H); 2.51 (s, 3H); calcd. for C₈ H₁₀ N₆ S.HBr: C,31.69; H, 3.66; N, 27.72; found: C, 31.46; H, 4.30; N, 27.28.

EXAMPLE 38 1-Acetyl-4-methylimidazole

A mixture of 50 g (609 mmol) of 4-methylimidazole in 250 ml of toluenewas stirred at room temperature under nitrogen and 239 g (304 mmol) ofacetyl chloride was added. The mixture was stirred at room temperaturefor 5 hours, filtered to remove insolubles and the filtrate concentratedgiving 19 g (50%) of 1-acetyl-4-methyl-imidazole as a yellow oil whichcrystallizes on standing. nmr (CDCl₃) (δ): 8.06 (s, 1H); 7.17 (s,1H);2.57 (s, 3H); 2.23 (s, 3H).

EXAMPLE 39 5-Acetyl-4-methylimidazole

A solution of 5.0 g (40.3 mmol) of 1-acetyl-4-methylimidazole in 700 mlof dry tetrahydrofuran was photolyzed in a quartz flask with a shortwave ultraviolet light source (254 nm) for 24 hours. The tetrahydrofuransolution was concentrated in vacuo to give an oil which waschromatographed on silica gel using 5% methanol in chloroform as eluentto give 1.91 g (38%) of 5-acetyl-4-methylimidazole as a white solid, mp140°-142°. nmr (CDCl₃ /D₆ DMSO) (δ): 7.45 (s, 1H); 2.52 (s, 3H); 2.48(s, 3H).

EXAMPLE 40 1-(4-Methyl-5-imidazolyl)-2-bromoethanone

A solution of 1.57 g (12.6 mmol) of 5-acetyl-4-methylimidazole in 15 mlof concentrated hydrobromic acid was warmed to 50° and a solution of2.01 g (12.6 mmol) of bromine in 15 ml of concentrated hydrobromic acidwas added over 0.75 hour. The mixture was stirred at 50° for 1.25 hour,then concentrated. The residue was triturated with isopropyl alcohol andthe white solid was collected by filtration. This amounted to 2.78 g(78%) of 1-(4-methyl-5-imidazolyl)-2-bromoethanone hydrobromide: nmr (D₆DMSO) (δ): 9.40 (s, 1H); 4.87 (s, 2H); 2.65 (s, 3H). This material wasconverted to its free base by stirring for 15 minutes in 50 ml ofsaturated sodium bicarbonate solution to give, after collection byfiltration and drying, 1-(4-methyl-5-imidazolyl)-2-bromoethanone as awhite powder.

EXAMPLE 41 2-Guanidino-4-(4-methyl-5-imidazolyl)thiazole hydrobromide

A mixture of 1.65 g (8.13 mmol) of1-(4-methyl-5-imidazolyl)-2-bromoethanone in 165 ml of acetone washeated until homogeneous. 0.96 g (8.13 mmol) of amidinothiourea wasadded and the mixture was heated at reflux for 1 hour. The mixture wasallowed to cool to room temperature and the resulting precipitate wascollected by filtration. This solid amounted to 0.98 g (40%) of2-guanidino-4-(4-methyl-5-imidazolyl)thiazole hydrobromide, mp 245°(dc); nmr (D₆ DMSO) (δ): 8.52 (s, 1H); 7.67 (b, 4H); 7.20 (s, 1H); 2.49(s, 3H). Anal Calcd. for C₈ H₁₀ N₆ s.HBr: C, 31.69, H, 3.66; N, 27.72;Found: C, 31.80; H, 3.90; N, 26.90.

EXAMPLE 42 1-Acetyl-2,4-dimethylimidazole

A solution of 9.6 g (0.10 M) of 2,4-dimethylimidazole in 50 ml ofchloroform and 50 ml of toluene was stirred at room temperature and 3.6ml (0.05 M) of acetyl chloride was added via syringe over 1 minute. Themixture was stirred at room temperature for 2 hours, then the mixturewas filtered to remove insoluble solids, and the filtrate concentratedleaving 6.9 g (100%) of 1-acetyl-2,4-dimethylimidazole as a whitecrystalline solid: nmr (CDCl₃) (δ): 7.00 (s, 1H); 2.68 (s, 3H); 2.57 (s,3H); 2.21 (s, 3H).

EXAMPLE 43 5-Acetyl-2,4-dimethylimidazole

A solution of 6.9 g (0.05 M) of 1-acetyl-2,4-dimethylimidazole in 700 mlof dry tetrahydrofuran was photolyzed in a quartz flask with a shortwave ultraviolet light source (254 nm) for 40 hours. The tetrahydrofuransolution was concentrated in vacuo to give an oil which waschromatographed on silica gel using 5% methanol in chloroform as eluentto give 2.8 g (41%) of 5-acetyl-2,4-dimethylimidazole as a white solid,mp 83°-87°. Recrystallization from isopropyl ether gave analyticallypure material, mp 87°-88°. nmr (CDCl₃) (δ): 2.53 (s, 6H); 2.40 (s, 3H).Anal. Calcd. for C₇ H₁₀ N₂ O: C, 60.85; H, 7.30; N, 20.27; found: C,60.66; H, 7.26; N, 20.09.

EXAMPLE 44 1-(2,4-Dimethyl-5-imidazolyl)-2-bromoethanone

A solution of 1.0 g (7.24 mmol) of 5-acetyl-2,4-dimethylimidazole in 15ml of concentrated hydrobromic acid was warmed to 50° and 1.16 g (7.25mmol) of bromine was added dropwise over 1 minute. The mixture was thenheated at 50°-60° for 1 hour. The mixture was concentrated and the solidresidue was triturated with 30 ml of saturated sodium bicarbonatesolution. The insoluble material was collected by filtration, washedwith water, and dried in vacuo to give 1.12 g (71%) of1-(2,4-dimethyl-5-imidazolyl)-2-bromoethanone as a white solid, mp128°-132°. nmr (D₆ DMSO) (δ): 4.40 (s, 2H); 2.27 (s, 3H); 2.13 (s, 3H).

EXAMPLE 45 2-Guanidino-4-(2,4-dimethyl-4-imidazolyl)thiazolehydrobromide hemihydrate

A solution of 1.0 g (4.6 mmol) of1-(2,4-dimethyl-5-imidazolyl)-2-bromoethanone in 50 ml of acetone waswarmed and 0.55 g (4.6 mmol) of amidinothiourea was added. The mixturewas heated at reflux for 1 hour, during which time a white solidprecipitated. The precipitate was collected, washed with acetone, anddried to give 1.12 g (77%) of2-guanidino-4-(2,4-dimethyl-5-imidazolyl)thiazole hydrobromidehemihydrate as a white solid, mp 273° (dc). nmr (D₆ DMSO) (δ): 8.4-7.2(b, 7H); 7.00 (s, 1H); 2.50 (s, 3H); 2.38 (s, 3H). Anal. Calcd. for C₇H₁₂ N₆ S.HBr.1/2H₂ O: C, 33.14; H, 4.33; N, 25.76; S, 9.83. Found: C,33.47; H, 4.19; N, 25.93; S, 9.91.

EXAMPLE 46 2-Guanidino-4-(2-N-phenylamino-4-imidazolyl)thiazole

A mixture of 2.3 g (8.5 mmol) of2-amino-1-(2-guanidino-4-thiazolyl)ethanone dihydrochloride, 2.0 g (17mmol) of N-phenylcyanamide and 40 ml of water was heated at 50° for 19hours. The dark solution was filtered to remove insolubles, and thefiltrate was washed with chloroform. The aqueous filtrate was made basicwith saturated sodium bicarbonate solution and the resulting precipitatewas collected by filtration, washed with water, ether, then acetonitrileto give a brown solid. This was dissolved in ethanolic hydrogen chlorideand ether was added resulting in the precipitation of a solid.Recrystallization from n-propanol/acetonitrile gave 479 mg of2-guanidino-4-(2-N-phenylamino-4-imidazolyl)thiazole dihydrochloride, mp245°-247° (dc). nmr (D₆ DMSO) (δ): 8.2-8.0 (b, 4H); 7.76 (s, 1H);7.4-7.0 (s+b, 5H). High resolution mass spectrum, calcd. for C₁₃ H₁₃ N₇S: 299.0953; found: 299.0964.

EXAMPLE 47 3-Bromo-4-ethoxy-3-buten-2-one

A mixture of 400 ml absolute ethanol and 60 ml toluene was heated toreflux and 20 ml of azeotrope was removed via a Dean Stark trap. To theethanol-toluene solution was added 33.0 g (0.2 mol) of3-bromo-4-hydroxy-3-buten-2-one and reflux was continued for 2 hoursduring which period three aliquots of 20 ml of ethanol-toluene wereremoved via the trap. The solution was concentrated in vacuo to give38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil. nmr(DMSO-6) (δ): 8.21 (s, 1H); 4.23 (q, 2H); 2.33 (s, 3H); 1.31 (s, 3H).

EXAMPLE 48 2-Hydroxymethyl-4-acetylimidazole

9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-buten-2-one was combined with5.53 (0.05 mol) of hydroxyacetamidine hydrochloride in 100 ml acetone toform a slurry. To the slurry at 25° was added 11.5 g (0.1 mol) of1,1,3,3-tetramethylguanidine over a period of 5 minutes. After stirringfor 48 hours the slurry was filtered and the mother liquors wereconcentrated in vacuo to an oil which was chromatographed on silica gel60 (E. Merck) using chloroform as eluent to give 1.48 g (21%) of2-hydroxymethyl-4-acetylimidazole, mp 147°-148°. nmr (DMSO-d₆) (δ): 7.73(s, 1H); 5.46 (very broad s, 1H); 4.5 (broad s, 2H); 2.4 (s, 3H).

EXAMPLE 49 2-Hydroxymethyl-4-bromoacetylimidazole hydrobromide

1.826 g (0.013 mol) of 2-hydroxymethyl-4-acetylimidazole was dissolvedin 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine wasadded. The reaction was warmed at 80° for 2 hours and then concentratedin vacuo to a solid. This material was triturated with isopropyletherand the resultant solid was collected by filtration and was washed withether and dried to give 2.2 g (56%) of2-hydroxymethyl-4-bromoacetylimidazole hydrobromide, mp 183° withdecomposition. nmr (DMSO-d₆) (δ): 8.8 (s, 1H); 4.8 (s, 2×2H).

EXAMPLE 50 2-Guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazolehydrobromide

1.78 g (0.0059 mol) of 2-hydroxymethyl-4-bromoacetylimidazolehydrobromide was dissolved in water and saturated sodium bicarbonatesolution was added to precipitate the free base. This material wascollected by filtration and dried and combined with 956 mg (0.0081 mol)of amidinothiourea in 60 ml acetone and heated to 70°. After 15 minutesheating a solid formed. The reaction mixture was cooled and theresultant solid was collected by filtration to give 1.65 g (87%)2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole hydrobromide,mp>310°. A sample was converted to the free base by dissolving in hotwater and adding sodium bicarbonate solid to pH 10 to precipitate2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole free base. Thismaterial was dried over toluene at high vacuum to give a light tansolid, mp 208°-209° with decomposition. nmr (DMSO-d₆) (δ): 7.16 (s, 1H);6.83 (broad s, 4H) 6.68 (s, 1H); 4.45 (s, 2H); 3.46 (very broad s, 1H).High resolution mass spectrum, calcd for C₈ H₁₀ N₆ OS: 238.0638; found:238.0654.

EXAMPLE 51

The gastric acid antisecretory activity of compounds of the presentinvention was determined in overnight fasted, conscious Heidenhain pouchdogs. Pentagastrin (Pentavlon-Ayerst was used to stimulate acid outputby continuous infusion into a superficial leg vein at doses earlierdetermined to stimulate near maximal acid output from the gastric pouch.Gastric juice was collected at 30 minute intervals following the startof a pentagastrin infusion and measured to the nearest 0.1 ml. Tencollections were taken for each dog during an experiment. Acidconcentration was determined by titrating 1.0 ml of gastric juice to pH7.4 with 0.1 N sodium hydroxide using an Autoburette and a glasselectrode pH meter (Radiometer).

Drug or vehicle was given intraveneously 90 minutes following the startof the pentagastrin infusion, at a dose of 1 mg/kg. Gastric acidantisecretory effects were calculated by comparing the lowest acidoutput after drug administration with the mean acid output immediatelybefore drug.

The results obtained showed that the compounds of Examples 4, 5, 6, 7,11, 13, 15, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 37, 41, 45 and50, all inhibited gastric acid secretion at least 15% at a dose of 1mg/kg.

EXAMPLE 52

The histamine-H₂ antagonist activity of compounds of the presentinvention was determined by the following procedure:

Guinea pigs are killed rapidly with a blow to the head, the heartremoved and the right atria dissected free. Atria are suspended,isometrically, in a temperature-controlled (32°±2°) tissue bath (10 mlcontaining oxygenated (95% O₂ ; 5% CO₂) Krebs-Henseleit buffer (pH 7.4)and are allowed to stabilize approximately one hour during which timethe tissue bath is flushed several times. Individual atrial contractionsare followed with a force-displacement transducer connected to acardiotachometer and Grass polygraph recorder. After obtaining adose-response curve to histamine, the bath containing each atrium isflushed several times with fresh buffer and the atria re-equilibrated tobasal rates. Following the return to basal rate, test compounds areadded at selected final concentrations and the histamine dose-responsecurve is again determined in the presence of antagonist. Results areexpressed as dose-ratios, the ratio of histamine concentrations requiredto produce one-half of maximal stimulation in the presence and absenceof antagonist, and the apparent dissociation constant of the H₂-receptor antagonist pA₂, is determined. The results obtained showedthat the compounds of Examples 4, 5, 6, 7, 11, 13, 15, 17, 20, 21, 22,23, 24, 25, 26, 27, 28, 31, 37, 41, 45, 46 and 50 have pA₂ values ofgreater than 5.7.

We claim:
 1. A compound of the formula ##STR5## or an acid addition saltthereof, wherein R' is hydrogen, hydroxymethyl, alkyl of 1 to 6 carbonatoms or --(CH₂)_(n) Ar, wherein n is an integer from 2 to 4; R" ishydrogen or methyl; and Ar is phenyl or phenyl monosubstituted withchloro, bromo, fluoro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3carbon atoms; and R₅ is halo.
 2. A compound of claim 1 wherein R' and R"are each hydrogen and R₅ is chloro or bromo.
 3. A compound of claim 1wherein R' is methyl, R" is hydrogen and R₅ is chloro or bromo.
 4. Acompound of claim 1 wherein R' is hydrogen, R" is methyl and R₅ ischloro or bromo.
 5. A compound of claim 1 wherein R' and R" are eachmethyl and R₅ is chloro or bromo.